The experiments proposed will utilize well characterized animal models to study the neurobiological basis for gender differences in drug abuse. Neuroadaptations associated with sensitization to psychomotor stimulants are thought to play an important role in the process of addiction. Furthermore, gender differences in the behavioral and neurochemica1 effects of psychomotor stimulants have been repeatedly reported to occur in rodents, and more recently in humans as well. In order to begin to understand gender differences in drug abuse, we believe that basic research on the role of gender and ovarian hormones in the response to acute and repeated exposure to cocaine is an important next step. Research on the acute behavioral response to psychomotor stimulants indicates that treatment of female rats with the ovarian hormone estrogen is sufficient to induce changes comparable to the effects of the estrous cycle. There are two hypotheses to be tested. The first is that there are gender differences in behavior induced by repeated exposure to the psychomotor stimulants and gender differences in self-administration of cocaine. The second is that estrogen potentiates both the acute and sensitized response to cocaine in female rats, enhancing these gender differences. In order to begin to understand the underlying neurological bases for gender differences in cocaine addiction there are two important factors that must be teased apart: l) differences between males and females (independent of gonadal hormones); and 2) whether gonadal hormones in either males or females affect responses to cocaine. In humans these factors are intermingled because chronic cocaine use can disrupt and even cause cessation of a woman's menstrual cycle. In such women, estrogen may play a role in acquisition of drug taking behaviors, but not in maintenance of these behaviors (since in women with amenorrhea the serum concentrations of estrogen are extremely low). On the other hand, more men than women abuse drugs, and many boys begin using drugs prior to sexual maturation. The experiments proposed will allow us to tease apart the relative importance of gender vs gonadal hormones in animal studies investigating the effects on cocaine-induced psychomotor behavior and cocaine self-administration.